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Inflammasomes and rheumatic diseases: evolving
concepts
P I Sidiropoulos, G Goulielmos, G K Voloudakis, E Petraki, D T Boumpas
Department of Rheumatology,
Clinical Immunology and Allergy,
University Hospital, Medical
School, University of Crete,
Heraklion, Greece
Correspondence to:
Prodromos Sidiropoulos,
Department of Internal
Medicine, Division of
Rheumatology, Clinical
Immunology and Allergy,
University of Crete, Medical
School, Voutes 71500,
Heraklion, Greece;
sidiropp@med.uoc.gr
Accepted 17 September 2007
Published Online First
5 October 2007
ABSTRACT
The realisation that the production of inflammatory
cytokines in inflammatory rheumatic diseases may be
induced by non-infectious endogenous signals has
encouraged researchers to explore mechanisms of innate
immunity and their contribution to the pathogenesis of
these diseases. The nucleotide-binding and oligomerisa-
tion domain (NOD)-like receptors (NLRs) sense patho-
gens, products of damaged cells or endogenous
metabolites and could potentially be involved in the
initiation, amplification and progression of the inflamma-
tory response in rheumatic diseases. NLRs are involved in
the regulation of innate immune responses with some of
them promoting the activation of inflammatory caspases
within multiprotein complexes, called inflammasomes. A
typical inflammasome consists of a sensor, an NLR
protein, an adaptor protein such as ASC (for apoptosis-
associated speck-like protein containing a caspase
recruitment domain (CARD)) and an effector protein that
is a caspase that activates pro-inflammatory cytokines
such as interleukin (IL)1band IL18. Recent data suggest a
role of the inflammasome in the pathogenesis of
autoinflammatory as well as inflammatory rheumatic
diseases such as juvenile chronic arthritis, adult onset Still
disease, rheumatoid arthritis and gout. Modulation of
these pathways may be a potential therapeutic target for
inflammatory rheumatic diseases.
The role of the immune system is to defend the
host from foreign invaders. Although once thought
to be a non-specific immune response, recently it
was found to perform with substantial specificity.
Innate immune recognition is mediated through a
limited number of receptors evolved to recognise
products born by pathogens, referred as pathogen-
associated molecular patterns (PAMPs).
1
PAMPs
are molecules vital for microbial survival with
preserved structure such as the bacterial lipopoly-
saccharide (LPS) and peptidoglycans (PGNs) or
viral RNA. Organisms have developed a group of
receptors that recognise these PAMPs, referred as
pathogen-recognition receptors (PRRs). Activation
of PRRs triggers inflammatory reactions of the
innate immune system, but in mammals also leads
to the release of mediators that activate the
adaptive immune system.
Two theories have been put forward for the
interpretation of the initiation of immune
responses: the pattern recognition theory and the
danger theory. The former suggests that microbial
non-self induces an innate immune response; this
in turn, triggers an adaptive immune response.
2
The danger theory holds that the host’s injured
cells release alarm signals that activate antigen-
presenting cells (APCs).
3
In the case of PRRs, both
propositions are operant. Innate immunity recep-
tors may recognise PAMPs and abnormal self or
danger signals such as DNA, RNA, or uric acid,
which should normally not be present outside the
cells or at certain locations within the cell.
4–6
TOLL-LIKE RECEPTORS (TLRS), NUCLEOTIDE-
BINDING AND OLIGOMERISATION DOMAIN (NOD)-
LIKE RECEPTORS (NLRS) AND RETINOIC ACID
INDUCIBLE GENE (RIG)-LIKE RECEPTORS (RLRS):
SENSORS OF PATHOGENS AND PRODUCTS OF
DAMAGED CELLS
Knowledge of PRRs has evolved in recent years and
they comprise extracellular and intracellular com-
ponents, namely the TLRs, the NLRs and the
RLRs. Among them, the TLR family is the most
studied.
78
TLRs survey the extracellular fluids and
endosomal compartments; upon stimulation by
specific bacterial, viral and fungal components,
they trigger gene products that control innate
immune responses and further direct the develop-
ment of antigen-specific acquired immunity,
mainly by regulating the function of dendritic cells
(DCs). Stimulation of TLRs results in the activa-
tion of different intracellular signalling cascades,
which generally activate NFkB and activated
protein-1 (AP-1) or type I interferon (IFN) synth-
esis.
9
In addition to recognising molecular patterns
associated with different classes of pathogens,
TLRs may also recognise a number of self proteins
and endogenous nucleic acids. Data originating
predominantly from animal models of autoim-
mune diseases and circumstantial data from
patients suggest that inappropriate activation of
TLR pathways by endogenous or exogenous
ligands may lead to the initiation and/or perpetua-
tion of autoimmune responses and tissue injury. In
MRL-lpr mice, TLR-3, TLR-7 and TLR-9 agonists
may exacerbate pre-existing immune complex
glomerulonephritis,
10
while immunocomplexes
containing IgG can stimulate rheumatoid factor
producing B cells through concomitant TLR-9 and
B cell receptor stimulation.
11
In patients with
systemic lupus erythaematosus (SLE), we have
recently reported that an increased proportion of B
cells and monocytes expressed TLR-9 among
patients with active compared to patients with
inactive disease; increased percentages of TLR-9
expressing B cells correlated with the presence of
anti-dsDNA antibodies.
12
Additional data demon-
strate that innate immune responses mediated by
TLRs may regulate inflammation in rheumatoid
synovial tissue. Mice deficient for the adaptor
molecule MyD88 are resistant to streptococcal
cell wall arthritis, and TLR2 deficient mice
have reduced disease severity.
13
In patients with
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rheumatoid arthritis (RA), TLRs are abundantly expressed in
the synovial tissue and TLR-2 activation of synovial fibroblasts
through bacterial peptidoglycans results in upregulation of
integrins, matrix metalloproteinases and inflammatory cyto-
kines (interleukin (IL)6, IL8).
14
Finally, ds-RNA released from
necrotic cells and heat shock proteins expressed in the synovial
tissue may activate TLR-3 and TLR-4 respectively.
The NLRs are intracellular receptors that sense pathogens or
danger signals and mount an inflammatory response.
5
They
comprise a group of 22 proteins that can be divided into 2 major
subfamilies, the NOD and the NTPases implicated in apoptosis
and multihistocompatability complex transcription (NACHT)
leucine-rich repeat protein (NALP) group; class II transactivator
(CIITA), the IL1B-converting enzyme (ICE)-protease activating
factor (IPAF) and the neuronal apoptosis inhibitor protein
(NAIP) are the other NLR group members. NALP, the major
subfamily, has 14 members (NALP1 to NALP14), while the
NOD subfamily consists of 5 members (NOD1 to NOD5).
They are also known as CATERPILLER proteins or NACHT-
leucine-rich repeat (LRR) proteins. NLRs have three structural
domains (fig 1).
15
Not surprisingly, there is significant crosstalk between TLR
and NLR signalling pathways. To give an example, TLR
stimulation results in pro-IL1band pro-IL18 production; these
are the main substrates for active caspase-1, which is produced
NLR-dependently upon inflammasome activation, culminating
in the production of mature IL1b. More recently, it has been
shown that caspase-1 is essential for TLR2 and TLR4 signalling,
through cleavage of MyD88 adaptor-like (Mal), an adaptor
protein downstream of the TLR2 and 4 signalling cascade.
16
While the main viral sensors on DCs are the antiviral TLRs
(TLR3, 7, 8 and 9), on cells other than DCs these appear to be the
RLRs.
17 18
RIG-1 and melanoma differentiation-associated gene-5
(MDA5) are two members of the RLRs that sense intracellular
dsRNA. RLRs have similarities with TLRs and NLRs. Following
activation, RLRs signal downstream through their CARD
domains to a CARD-containing adaptor protein interferon b
promoter stimulator (IPS1), leading to IFNa/bproduction.
INFLAMMASOMES: STRUCTURE AND EXPRESSION
Caspases are a group of aspartate-specific proteases involved in
apoptotic or inflammatory pathways. Inflammatory caspases
(known as group I caspases) are caspase-1, caspase-4 and
caspase-5. Caspases are produced in cells as catalytically inactive
zymogens and undergo proteolytic processing during activation.
Caspase-1 mediates pro-IL1bmaturation,
19 20
as well as pro-IL18
and possibly IL33.
21
Caspase-5 is a component, together with
caspase-1, of the NALP-1 inflammasome that cleaves pro-IL1b
Figure 1 Nucleotide-binding and oligomerisation domain (NOD)-leucine-rich repeat (LRR) and inflammasome structures. NOD-like receptors (NLRs)
have three structural domains.
15
A. The LRR domain at the C-terminus. B. The intermediary NTPases implicated in apoptosis and multihistocompatability
complex transcription (NACHT) domain. C. The N-terminal domain that can be a pyrin domain (PYD), a caspase recruitment domain (CARD) or a
baculovirus inhibitor-of-apoptosis protein repeat domain (BIR). The LRR domain is considered as the ligand-sensing motif, thus involved in the
interaction with pathogen-associated molecular patterns (PAMPs), in analogy to Toll-like receptors (TLRs). The NACHT domain is responsible for the
oligomerisation and activation of NLRs. The PYD or CARD domain of NLR is the link to downstream adaptors (such as apoptosis-associated speck-like
protein containing a CARD (ASC)) or effectors (such as caspase-1). The BIR domain is proposed to act as caspase inhibitor.
99
During NACHT leucine-
rich repeat protein (NALP)3 and NALP1 inflammasome activation, NALP3 or NALP1 interact through PYD–PYD homotypic interactions with ASC,
resulting in its activation.
25
Subsequently, the CARD domain of ASC interacts with the CARD domain of caspase-1 and mediates its activation. Of note,
NALP1 may also activate directly the caspase-5 through its C-terminal CARD domain. In contrast, NALP3 does not simultaneously activate caspase-5,
but NALP3 can recruit a second capsase-1 through the CARD domain of CARD inhibitor of nuclear factor kB activating ligand (CARDINAL), a component
of the NALP3 inflammasome.
40
Interestingly, interleukin 1B-converting enzyme (ICE)-protease activating factor (IPAF), that can on its own sense PAMPs
possesses a CARD domain at the N-terminal and thus may directly activate caspase-1 without ASC recruitment (‘‘IPAF inflammasome’’).
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(see below). Caspase-5 may also have a regulatory role in
tumourigenesis. Caspase-5 cleaves Max, a component of the
Myc/Max/Mad network of transcription factors that is
frequently deregulated in tumours.
22
Frameshift mutations of
caspase-5 are frequently found in endometrial carcinoma.
23
The puzzle of the machinery involved in the activation of
caspases has recently been expanded with the characterisation
of certain of NLRs proteins, which are involved in the formation
of caspase activating complexes referred as inflammasomes
(fig 2).
24
NLR proteins that, upon specific stimuli engagement,
promote the assembly of inflammasome include NALP1,
NALP3, IPAF and NAIP. A typical inflammasome consists of a
NLR protein serving as a sensing protein, one or more adaptor
proteins (ie, apoptosis-associated speck-like protein containing a
CARD (ASC)) and one or more inflammatory caspases acting as
effectors (fig 1).
25
The main adaptor molecule in the interface of
NLRs and caspase-1 activation is ASC, a bipartite molecule
containing a PYD and a CARD domain. Upon ligand sensing
(table 1), NLRs are activated and expose the effector domains;
CARD or PYD. Those domains, through homotypic interactions
recruit molecules containing CARD or PYD, bringing them in
close proximity to each other, ultimately activating them. These
molecules may be adaptors, like ASC protein, or effector caspases.
Three human inflammasomes have been described, named
from the NLR protein involved: the NALP1 inflammasome,
activates caspase-5 and caspase-1; and the NALP3 and IPAF
inflammasomes, both of which activate caspase-1 (fig 1). Of
note, there is no evidence to support whether ligands of
microbial origin bind directly to NLRs or, as has been proposed
for the plant NLR homologues, this is an indirect sensing.
26 27
Human studies have shown that NALP1 and NALP3 have
distinct and separate expression profiles in human tissues.
28
Granulocytes, T cells, B cells and dendritic cells express NALP1
and NALP3. NALP1 is present in glandular epithelial structures
(stomach, gut, lung) while NALP3 is expressed mainly in non-
keratinising epithelia (oropharynx, oesophagus and ectocervix).
Major questions regarding NLRs to be clarified include: (1)
what are the exact subcellular localisation and trafficking of
NLRs; (2) do NLRs act as direct receptors of PAMPs or do they
sense PAMPs bound to adaptor proteins?and (3) how they may
be involved in mounting adaptive immune responses?
REGULATION OF THE INFLAMMASOME
Although IL1bis essential for the control of infections or self
danger signals, its uncontrolled production could be harmful.
Thus, delineation of the regulators of the inflammasome could
be of therapeutic potential. To this end, different proteins have
been proposed to interfere with inflammatory caspases activa-
tion. The first type of proteins considered as inflammasome
regulators are characterised by the presence of a CARD domain
highly similar to that of caspase-1.
29
These proteins are thought
to prevent recruitment and activation of the caspase by the
Figure 2 Activation of inflammasome by exogenous or endogenous signals results in caspase activation and interleukin (IL)1bor IL18 production.
Two signals are essential for mature IL1 secretion.
100
In signal 1, immune cells stimulated with Toll-like receptor (TLR) ligands, produce pro-IL1band
other inducible components of inflammasome (caspase-11). These cells are primed to receive the second signal, which through inflammasome will
activate caspase-1 to cleave pro-IL1bto mature IL1b. Upon ligand sensing (signal 2), nucleotide-binding and oligomerisation domain (NOD)-like
receptors (NLRs) are activated and expose the effector domains, caspase recruitment domain (CARD) or pyrin domain (PYD), which, through homotypic
interaction, recruit molecules containing CARD or PYD, bringing them in close proximity to each other leading thus to their activation. These molecules
may be adaptors, such as apoptosis-associated speck-like protein containing a CARD (ASC) protein, or effector caspases.
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adaptor ASC or by IPAF, through CARD–CARD interactions.
This group includes the decoy caspase-1 genes present in the
human caspase-1 locus, such as iceberg, INCA, COP and caspase-
12.
30–33
Other inhibitors of the inflammasome are characterised by
the presence of PYD domain and are thought to interfere with
PYD–PYD interactions between ASC and NALPs. Pyrin, the
protein involved in familial Mediterranean fever (FMF), is
considered as one of inflammasome regulators. ‘‘Pyrin-only’’
proteins (POP), are attractive negative regulators of PYD-
mediated functions. Recently Johnston et al reported that
M13L-PYD a POP from myxoma virus, inhibits caspase-1
dependent IL1 production and NFkB activity.
34
Deletion of
M13L inhibited virus replication in vivo.
INFLAMMASOME AND ADAPTIVE IMMUNE RESPONSES
Inflammasome activation has been examined so far in the
context of the innate immunity in a variety of experimental
systems of infections
4 6 35–39
and autoinflammatory diseases.
40
Its
role in adaptive immune system reactions is less clear. Recently
reported data support a critical role for NALP3-inflammasome
in mounting contact hypesensitivity reactions, a T cell mediated
cellular immune response to repeated epicutaneous exposure of
contact allergens, that can be divided in two phases, the
sensitisation and elicitation. The roles of IL1band caspase-1 in
the sensitisation phase
41 42
have been described earlier.
43
Recent
data suggest that NALP3–/– and ASC–/– animals elicit
significantly impaired hypersensitivity response to the hapten
trinitrophenylchloride compared to wild type animals.
44
Furthermore, by the use of bone marrow chimera experiments,
it was shown that NALP3 and ASC are essential in the
sensitisation phase. Key components of the inflammasome are
present in human keratinocytes; contact sensitisers such as
trinitrochlorobenzene, induce ASC/caspase-1 dependent IL1b
and IL18 processing and secretion.
45
It has been known for several years that IL1bmay have an
adjuvant capacity; in mice immunised with protein antigens
together with IL1, serum antibody production was enhanced.
46
By contrast, it has recently been shown that adjuvants used in
humans act through inflammasome. Thus, aluminium hydro-
xide (Alum), an adjuvant approved for routine use in humans,
may act through activation of caspase-1.
47
Human peripheral
blood mononuclear cells (PBMCs) and DCs treated with a
combination of various TLR ligands and aluminium, activated
caspase-1 and produced large amounts of IL1band IL18. Alum-
induced IL1band IL18 production was not due to enhanced TLR
signalling but rather reflected caspase-1 activation; experiments
with MyD88 deficient mouse DC showed that the Alum effect
was MyD88 independent, further supporting that Alum
mediated its signalling independently of TLR.
Signalling through TLRs, such as for example TLR4, activates
the MyD88-dependent pathway, resulting in inflammatory
gene transcription, and the Trif-dependent cascade resulting
in interferon regulatory factor 3 (IRF3) activation and type I
IFN production.
9
An interplay of type I IFN and inflamma-
some activation has been reported recently;
48
upon infection
with cytosolic bacteria adequate production and signalling of
type I IFN is required for effective inflammasome activation.
Given the broad role of type I IFN in immunity to viruses
and autoimmunity, this complex interplay needs further
investigation.
INFLAMMASOME-DEPENDENT INFLAMMATORY CYTOKINES
AND AUTOIMMUNITY
The role of IL1bin the pathophysiology of rheumatic diseases
such as RA is well established.
49
IL1bis present in inflamed
synovium of mice with antigen-induced and collagen-induced
arthritis,
50 51
while intra-articular ex vivo gene transfer of IL1bin
rabbits resulted in a highly aggressive arthritis.
52
In synovial
biopsies from patients with RA, IL1bhas been found in areas of
macrophages and fibroblasts.
53
In spite of strong evidence of
IL1binvolvement in RA pathophysiology, the clinical efficacy of
IL1 blockade targeting IL1 receptor antagonist was rather
disappointing. A novel agent that blocks IL1b, IL1 TRAP
54
is
currently under investigation in patients with RA or cryopyrin-
associated periodic syndromes.
In addition to its multiple pro-inflammatory properties, IL1b
also promotes autoreactivity by several mechanisms. In immune
complex disease such as lupus, IL1bmay participate in renal
tissue injury because it is essential for the production of
monocyte chemotactic protein-1 (MCP-1) by resident renal
cells.
55
IL1b/IL1R signalling may affect adaptive immune
responses and promote autoreactivity affecting: (1) production
of cytokines by DCs and thus T cell priming;
56
(2) induction of
CD40 ligand and OX40 expression on T cells and thus T and B
cell interaction;
57
and (3) affecting directly autoreactive effector
T cells.
58
By contrast, IL18 is thought to be involved in the pathogen-
esis of many autoimmune diseases in several animal models,
such as the non-obese diabetic (NOD) mouse,
59
the collagen-
induced arthritis;
60 61
moreover in lupus prone MRL lpr/lpr
animals that were repetitively vaccinated with IL18 cDNA
coding the murine IL18 precursor were protected from devel-
oping the disease.
62
In humans, elevated levels of IL18 have been
found in affected tissues in patients with Crohn disease
63 64
and
RA.
65 66
Table 1 Ligands of inflammasomes
Inflammasome
NALP3 Microbial motifs:
Bacterial muramyl dipeptide
86
Bacterial RNA
39
Antiviral compounds (imidazoquinoline R837 and R848)
39
Double-stranded RNA and viral RNA
87
Bacteria:
Staphylococcus aureus
6
Listeria monocytogenes
6
Viruses:
Sendai and influenza
87
Toxins:
Maitotoxin (potassium ionophore)
6
Nigericin (marine toxin)
6
Aerolysin (Aeromonas species)
36
Host danger signals:
Uric acid
4
ATP
6
Low intracellular potassium concentration
88
UVB-induced activation of keratinocytes
89
Ipaf Microbial motifs:
Cytosolic flagellin
38 90
Bacteria:
Salmonella Typhimurium
35
Legionella pneumophila
91
NALP1 (murine) Toxins:
Bacillus anthracis lethal toxin
92
NALP, NTPases implicated in apoptosis and multihistocompatability complex
transcription (NACHT) leucine-rich repeat protein; UVB, ultraviolet B.
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INFLAMMASOME AND AUTOINFLAMMATORY DISEASES
(TABLE 2)
FMF and tumour necrosis factor receptor-associated periodic
syndrome (TRAPS) are the two prototypes of a group of
diseases referred as systemic autoinflammatory diseases. These
represent a group of inherited disorders characterised by
unprovoked inflammation and absence of autoantibodies or
antigen-specific T cells.
67
FMF is an autosomal recessively
inherited disease caused by mutations in the MEFV gene that
encodes for a protein known as the pyrin (or marenostrin)
(table 2). To date over 117 MEFV mutations have been reported.
Pyrin consists of four domains and all of them can facilitate
protein interactions: the PYD domain, the B-box zinc finger
domain, a coiled-coil domain and a C-terminal 30.2/rfp/SPRY
domain (also known as PRYSPRY domain).
Pyrin seems to be one of the regulators of inflammasome
activation, with most data supporting an inhibitory effect on
IL1bproduction. More specifically, pyrin interacts through its
PYD domain with PYD domain of ASC, and negatively
regulates inflammasome by competing for ASC. The murine
RAW monocytic cell line transfected by full-length mouse pyrin
had reduced IL1bsecretion, while mouse peritoneal macro-
phages expressing a truncated pyrin exhibited increased IL1b
compared to wild type controls.
68
Of note, a high percentage of
pyrin mutations associated with FMF are located in the C-
terminal B30.2 domain, whose functional importance has just
begun to be investigated. Chae et al found that human pyrin can
directly (ASC independently) inhibit caspase-1; this interaction
is mediated through the B30.2 domain and interaction results in
reduced IL1bsecretion.
69
Supporting the hypothesis of pyrin as a
negative regulator of inflammasome, FMF-associated pyrin
mutants located in the B30.2 domain could not reduce IL1b
secretion. By contrast, Yu et al showed that in transfected 293T
human kidney embryonic cells, pyrin may actually assemble an
inflammasome complex and activate caspase-1 and IL1b, thus
acting as a proinflammatory protein.
70
Finally, Papin et al have
recently found that the SPRY domain of pyrin interacts with
NALP3, caspase-1 and pro-IL1 and inhibits caspase-1 dependent
IL1b production,
71
adding more complexity to the pyrin
involvement in IL1 homeostasis.
Blockade of IL1bwith IL1 receptor antagonist (anakinra) has
been tried in patients with FMF. Although there are case reports
showing clinical benefit,
69 72
there are resistant cases. An
ongoing phase-II clinical trial of IL1 TRAP, a novel IL1 inhibitor,
sponsored by the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS),
(ClinicalTrials.gov identifier NCT00094900) explores the clin-
ical benefit of IL1bblockade in patients with FMF.
CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)
The group of autoinflammatory diseases has been expanded to
include disorders associated with mutations in the NALP3
protein (or cryopyrin), also called CAPS. CAPS comprises of
familial cold autoinflammatory syndrome (FCAS), Muckle–
Wells syndrome (MWS), neonatal onset multisystem inflam-
matory disease (NOMID) also called chronic infantile neurolo-
gical cutaneous and articular syndrome (CINCA).
73
Missense
mutations in the NACHT domain of NALP3 are involved in all
three diseases.
74 75
Since the original genetic identification
74
more
than 30 missense mutations have been identified.
76
These
mutations confer a gain of function to the NALP3 protein that
results in constitutively active NALP3, that results in aberrant
maturation of IL1b.
40
The fundamental role of IL1bin these
diseases has been shown by the profound therapeutic efficacy of
IL1binhibition through IL1 receptor antagonist (IL1Ra,
anakinra) in patients with MWS, FCAS or NOMID.
77–79
GOUT AND PSEUDOGOUT
Gout is one of the most acute inflammatory arthritides,
characterised by tissue deposition of monosodium urate
(MSU) crystals. Recently it has been shown that MSU
inflammation is inflammasome-dependent, while MyD88-
dependent IL1 receptor signalling is essential for inflammatory
responses. NALP3 inflammasome is essential for IL1bproduc-
tion through ASC and caspase-1 recruitment upon MSU
challenge. Martinon et al
4
showed that mouse macrophages
from NALP3–/–, ASC–/– or caspase-1–/– mice produced
significantly less mature IL1b, compared to wild type animals
when challenged with MSU. The same was true when calcium
pyrophosphate dehydrate (CPPD) crystals were used as inflam-
masome trigger. By contrast, none of the 11 TLRs, the
extracellular sensors of innate immunity, had any involvement
in sensing MSU crystals.
80
Nevertheless, one cannot exclude
TLR involvement in promoting IL1bprecursor synthesis. The
IL1breleased then mediates IL1R signalling and MyD88-
dependent NFkB activation, resulting in the transcription of
neutrophil-recruiting chemokines such as IL8, S100 and macro-
phage inflammatory protein-2 (MIP-2). However, the mechan-
ism of downregulation of acute gouty attacks remains poorly
understood. The role of IL1bin acute gout has been reinforced
by the clinical effectiveness of IL1breceptor blockade in a small
open label study.
81
In this study, 10 patients with gout who
Table 2 Inflammatory diseases associated with inflammasome and related proteins
Disease Inflammasome involvement References
Systemic onset juvenile
arthritis (SoJIA)
Human studies in patients with SoJIA showing: (1) increased expression of IL1bfrom PBMCs upon stimulation and
(2) cases of clinical efficacy of recombinant IL1Ra
Pascual et al, Verbsky et
al
82 93
Gout/CPPD Defective crystal-induced IL1bactivation in knockout animals for NALP3, ASC or caspase-1; indirect evidence from
human studies proving effectiveness of IL1Ra in gout
Martinon et al,Soet al
481
Familial Mediterranean fever Mutations of pyrin, an inflammasome inhibitor, may lead to defective downregulation of inflammasome activation
or to direct activation of caspase-1
Chae et al, The French FMF
Consortium, The International
FMF Consortium
68 69 94 95
Cryopyrin associated periodic
syndromes (CAPS)
Mutated NALP3 (cryopyrin) has enhanced propensity to induce caspace-1 Hoffman et al
74
Crohn disease, Blau syndrome NOD2 mutations are identified in 10–15% of patients with Crohn disease: (1) Loss of function NOD2 mutations may
lead to defective macrophage function, persistent intracellular infection of macrophages and chronic T cell
stimulation; (2) gain of function NOD2 mutations may enhance the sensitivity of macrophages to MDP, thus
potentiating NFkB activity and inflammatory responses
Hugot et al, Oruga et al,
Baumgart et al
96–98
ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); CPPD, calcium pyrophosphate dihydrate; IL, interleukin; IL1Ra, IL1 receptor
antagonist; MDP, muramyl dipeptide; NALP, NTPases implicated in apoptosis and multihistocompatability complex transcription (NACHT) leucine-rich repeat protein; NFkB, nuclear
factor kB; NOD, nucleotide-binding and oligomerisation domain.
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could not tolerate or had failed standard anti-inflammatory
therapies were treated for 3 consecutive days with 100 mg/day of
anakinra; all 10 patients responded well with no adverse events.
SYSTEMIC ONSET JUVENILE IDIOPATHIC ARTHRITIS (SOJIA)
SoJIA, is a form of juvenile idiopathic arthritis characterised by
prominent systemic symptoms. IL1bis a key inflammatory
cytokine in disease pathophysiology. Pascual et al reported that
PBMCs from SoJIA upon stimulation secrete high amounts of
IL1bcompared to control, but not TNFaor IL6.
82
Microarray
analysis of healthy PBMCs after incubation with serum from
patients with active SoJIA , showed that among the genes that
were upregulated was the IL1bgene (by a mean of 8.2-fold) as
well as other IL1 cytokine/cytokine receptor family genes and
other innate immunity genes (chemokines, fibronectin etc). The
clinical efficacy of recombinant ILRa confirms the significance
of IL1bin the inflammatory cascade in SoJIA.
83
INFLAMMASOME AS A THERAPEUTIC TARGET
As already discussed, inhibition of the end product of inflamma-
some activation, namely IL1b, has been proved clinically effective
in diseases such as CAPS,
77 78
adult onset Still disease
83
and more
recently in gout .
81
Although direct IL1binhibition is appealing,
alternative ways to inhibit inflammasome activation could be of
interest. It is apparent that there are multiple proteins and
regulators that participate in the activation of inflammasome; this
offers the opportunity for intervention for inhibition of inflam-
matory caspases activation. For example, novel regulators of
inflammasome activation could be applied to inhibit caspase
activation. Moreover, caspase inhibitors, either pan-caspase
inhibitors or specific caspase-1 inhibitors, have been developed
and assessed by different pharmaceuticals. For example, caspase-1
inhibitor Z-YVAD-FMK inhibits in vitro IL1bproduction from
monocytes from patients with familial cold autoinflammatory
syndrome.
84
Other caspase inhibitors have been tested in animal
models or even in clinical trials of rheumatic diseases, such as RA.
85
Since inflammasome activation is the second signal for IL1b
production, the first one is mediated through TLR4 signalling
(resulting in pro-IL1bproduction), it is conceivable that the
combination of inhibitors in TLR4 signalling cascade could be
important for suppressing IL1bproduction.
CONCLUSIONS
The interplay between different pathogen sensors on the cell
surface (TLRs) and in the cytoplasm (NLRs) has revealed the
complex mechanisms used by the organisms to mount effective
immune responses to pathogens and endogenous danger signals.
Inflammasome products are also essential components of the
adaptive immune responses. Together these data support the
notion that a diverse spectrum of inflammatory rheumatic
diseases irrespective of their aetiology (autoimmune, autoin-
flammatory or crystal-induced) may share common inflamma-
tory pathways. Improved understanding of the mechanisms of
inflammasome activation and regulation will provide insights in
the pathophysiology of many chronic inflammatory diseases
and may uncover novel therapeutic targets.
Competing interests: None declared.
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